This proposal examines the development of a solid phase combinatorial method for the synthesis of Boxazomycin and a large library of related analogs. The Boxazomycin class of antibiotics is a recently discovered antimicrobial natural product and has a potent, broad spectrum activity against several common types of bacteria. (e.g. sub-micromolar activity against Staph. Aureus) This class of antibiotics is especially exciting because for several strains of bacteria, the activity equals or exceeds that of the current arsenal of antibiotics. The first goal of this proposal is to develop a novel solid phase synthesis of the core structure of Boxazomycin. The synthesis will be developed according to the following criteria. First, the core structure is proposed to be divided into building blocks that can be attached to a polymer resin in a sequential fashion. Second, the reactions proposed at each step will be general enough to accommodate a diversity of functional groups on each building block. Third, the building blocks must be commercially available or accessible in only a few synthetic steps. The second goal of the proposal is the implementation of a lead-structure based combinatorial synthesis of new compounds based on the Boxazomycin core structure. The purpose is to create a focused library of novel analogs of the Boxazomycin antibiotics for structure-activity relationship studies and for the identification of new therapeutically useful antibiotic compounds.